PROJECT SUMMARY Chronic kidney disease (CKD) affects >10% of the adult US population, costs tens of billions of dollars annually, and can lead to progressive kidney failure, cardiovascular disease (CVD), and early mortality. CKD is not a single entity but rather a heterogeneous condition with a wide spectrum of underlying causes, pathologic and clinical manifestations, and rates of progression. Because of the paucity of kidney biopsy samples from patients with common forms of CKD and the acknowledged limitations of animal models, our understanding of the pathology and molecular mechanisms of CKD is limited. Deeper understanding of human CKD will require investigation of kidney tissue from patients with CKD, using rapidly evolving techniques in molecular pathology. In this proposal we have established a multidisciplinary investigative team and outline plans for a multicenter CKD recruitment site for the Kidney Precision Medicine Project (KPMP) [RFA-DK-16-026] involving Brigham and Women?s Hospital, Joslin Diabetes Center, Beth Israel Deaconess Medical Center, and Massachusetts General Hospital. The proposal builds upon an established infrastructure, the Boston Kidney Biopsy Consortium (BKBC, R01DK093574) that has successfully enrolled, collected biospecimens, and longitudinally followed > 800 patients undergoing native kidney biopsy at the four institutions. We will share plasma, urine, DNA, RNA, and archival kidney tissue specimens from the BKBC with the KPMP in order to accelerate progress in the UG3 phase and beyond. We will also share samples from U01DK104308, a study that collects intraoperative kidney tissue samples from non-cancer cortex during nephrectomy for research in kidney fibrosis. For the UG3 phase we propose participating in collaborative discussions to define the scientific objectives and to address the ethics and safety of kidney biopsy in CKD. Pilot studies in the UG3 phase will include research biopsies in patients with CKD who do not typically undergo kidney biopsy, and research cores from patients undergoing clinically indicated biopsies for CKD. In the UH3 phase, we propose expanding the study to include larger numbers of research biopsies across different stages of CKD. We also propose biopsies in individuals with longstanding Type 1 diabetes mellitus with no evidence of kidney pathology, in order to identify molecular underpinnings of protection against diabetic kidney disease. We also outline a proposal for repeat biopsies in 10 participants with rapid annual loss of estimated GFR (>5 ml/min/year) and in 10 participants with no change in estimated GFR (<1ml/min/year). We are committed to collaborative protocol development, sharing best practices, and team science to achieve the KPMP?s objectives of advancing precision medicine to improve the lives of our patients with and at risk for CKD. The proposed research plan, by improving our understanding of CKD pathophysiology, has the potential to dramatically impact public health.